Candida albicans is a ubiquitous fungal symbiont that resides on diverse human barrier surfaces. Both mammalian and fungal cells can convert arachidonic acid into the lipid mediator, prostaglandin E2 (PGE2), but the physiological significance of fungus-derived PGE2 remains elusive. Here we report that a C. albicans mutant deficient in PGE2 production suffered a loss of competitive fitness in the murine gastrointestinal (GI) tract and that PGE2 supplementation mitigated this fitness defect. Impaired fungal PGE2 production affected neither the in vitro fitness of C. albicans nor hyphal morphogenesis and virulence in either systemic or mucosal infection models. Instead, fungal production of PGE2 was associated with enhanced fungal survival within phagocytes. Consequently, ablation of colonic phagocytes abrogated the intra-GI fitness boost conferred by fungal PGE2. These observations suggest that C. albicans has evolved the capacity to produce PGE2 from arachidonic acid, a host-derived precursor, to promote its own colonization of the host gut. Analogous mechanisms might undergird host-microbe interactions of other symbiont fungi.

Neutrophil responses against pathogens must be balanced between protection and immunopathology. Factors that determine these outcomes are not well-understood. In a mouse model of genital herpes simplex virus-2 (HSV-2) infection, which results in severe genital inflammation, antibody-mediated neutrophil depletion reduced disease. Comparative single-cell RNA-sequencing analysis of vaginal cells against a model of genital HSV-1 infection, which results in mild inflammation, demonstrated sustained expression of interferon-stimulated genes (ISGs) only after HSV-2 infection primarily within the neutrophil population. Both therapeutic blockade of IFNα/β receptor 1 (IFNAR1) and genetic deletion of IFNAR1 in neutrophils concomitantly decreased HSV-2 genital disease severity and vaginal IL-18 levels. Therapeutic neutralization of IL-18 also diminished genital inflammation, indicating an important role for this cytokine in promoting neutrophil-dependent immunopathology. Our study reveals that sustained type I interferon (IFN) signaling is a driver of pathogenic neutrophil responses and identifies IL-18 as a novel component of disease during genital HSV-2 infection.

Neutrophil responses against pathogens must be balanced between protection and immunopathology. Factors that determine these outcomes are not well-understood. In a mouse model of genital herpes simplex virus-2 (HSV-2) infection, which results in severe genital inflammation, antibody-mediated neutrophil depletion reduced disease. Comparative single cell RNA-sequencing analysis of vaginal cells against a model of genital HSV-1 infection, which results in mild inflammation, demonstrated sustained expression of interferon-stimulated genes (ISGs) only after HSV-2 infection primarily within the neutrophil population. Both therapeutic blockade of IFNα/β receptor 1 (IFNAR1) and genetic deletion of IFNAR1 in neutrophils concomitantly decreased HSV-2 genital disease severity and vaginal IL-18 levels. Therapeutic neutralization of IL-18 also diminished genital inflammation, indicating an important role for this cytokine in promoting neutrophil-dependent immunopathology. Our study reveals that sustained type I IFN signaling is a driver of pathogenic neutrophil responses, and identifies IL-18 as a novel component of disease during genital HSV-2 infection.

1314 Candida albicans is a ubiquitous fungal symbiont that resides on diverse human barrier surfaces. Both 15 mammalian and fungal cells can convert arachidonic acid into the lipid mediator, prostaglandin E2 16 (PGE 2 ), but the physiological significance of fungal-derived PGE 2 remains elusive. Here we report 17 that a C. albicans mutant deficient in PGE 2 production suffered a loss of competitive fitness in the 18 murine gastrointestinal (GI) tract and that PGE 2 supplementation mitigated this fitness defect.19 Impaired fungal PGE 2 production affected neither the in vitro fitness of C. albicans nor hyphal 20 morphogenesis and virulence in either systemic or mucosal infection models. Fungus-derived PGE 2 21 improved intra-GI fitness of C. albicans by diminishing the killing of C. albicans by phagocytes.22 Consequently, ablation of colonic phagocytes abrogated the fitness boost conferred by fungal PGE 2 .23 These observations suggest that C. albicans has evolved the capacity to produce PGE 2 from 24 arachidonic acid, a host-derived precursor, to promote its own colonization of the host gut. Analogous 25 mechanisms might undergird host-microbe interactions of other symbiont fungi. 263 27 Author Summary 28 29 Candida albicans is a symbiont fungus that resides in the gut of a majority of people without 30 provoking disease. However, resident C. albicans can bloom and turn pathogenic in a subset of 31 individuals who are immunocompromised due to infections or chemotherapy or who suffer a disruption 32 of their intestinal microbial community due to antibiotic use. However, the fungal and host factors that 33 regulate the fitness of C. albicans as a symbiont or an invasive pathogen remain poorly understood.34 Here we focused on the physiological role of fungus-derived prostaglandin E2 (PGE 2 ) in the fitness of 35 C. albicans using a PGE 2 -deficient C. albicans strain and mouse models of infections and intestinal 36 symbiosis. We found that fungal PGE 2 , contrary to previously described functions of promoting 37 virulence, played no role in fungal pathogenicity in vivo. Instead, fungal PGE 2 specifically augmented 38 the ability of C. albicans to colonize the gut, in part by reducing fungal killing by intestinal phagocytes.39 Our results suggest that fungal PGE 2 synthetic pathways may be prophylactically targeted in 40 individuals susceptible to invasive infections.41 4 42 Introduction 43 44 Candida albicans is one of the most successful fungal symbionts in humans, colonizing 40-45 80% of individuals in industrialized nations and typically representing the predominant species within 46 the fungal microbiota [1, 2]. In healthy people, C. albicans dwells on diverse barrier sites of the body, 47 including the oral cavity, skin, female reproductive tract, and the intestines, where it does not cause 48 symptomatic disease [1, 2]. However, C. albicans can turn pathogenic and result in mucosal or life-49 threatening invasive bloodstream infections under a variety of conditions that compromise host 50 immunity, damage barr...